Targeting PI3‐kinase (PI3K), AKT and mTOR axis in lymphoma

Abstract

Targeted therapy represents a transformation in oncology, a field that has relied primarily on non-selective cytotoxic therapies. Phosphatidylinositol 3-kinase (PI3K) is a family of ubiquitous signalling molecules involved in a wide variety of cellular processes and likewise, in a broad selection of human cancers. The discovery that the p110-δ form of PI3K is differentially expressed in normal and malignant lymphocytes has led to the development of specific inhibitors that are currently in clinical trials for lymphoma. Downstream effectors of PI3K, including v-akt murine thymoma viral oncogene homolog 1 (AKT; also termed AKT1) and mechanistic target of rapamycin (serine/threonine kinase) (mTOR) are similarly important in lymphoma, and agents targeting these components of the PI3K-AKT-mTOR axis are also underway, although at earlier stages of development. In this review we examine the role of PI3K-AKT-mTOR in normal and malignant lymphocytes, as well as the preclinical and clinical status of a number of inhibitors of this pathway.

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

“…Furthermore, PI3K, a common intracellular downstream effector of glucose and insulin, was shown to be associated with CFTR activation (Blachly and Baiocchi 2014). Blachly and Baiocchi (2014) showed that PI3K is involved in the modulation of CFTR by insulin in kidney cells, highlighting a possible association between the lack of insulin in the STZ‐induced diabetic animal model and CFTR dysfunction.…”

“…Blachly and Baiocchi (2014) showed that PI3K is involved in the modulation of CFTR by insulin in kidney cells, highlighting a possible association between the lack of insulin in the STZ‐induced diabetic animal model and CFTR dysfunction. Nevertheless, more studies on the complex relationship between the endocytic machinery components and diabetes features, such as hyperglycemia, lack of insulin, and albumin overload, are indeed necessary (Blachly and Baiocchi 2014). …”

4EBP1/c-MYC/PUMA and NF-κB/EGR1/BIM pathways underlie cytotoxicity of mTOR dual inhibitors in malignant lymphoid cells

“…[1][2][3][4] The observation that mTOR is aberrantly activated in a variety of malignancies has generated intense interest in this kinase as a target for antineoplastic therapy, particularly for lymphoid malignancies. 1,3,[5][6][7][8][9][10][11] Over the last decade, rapamycin-based mTOR inhibitors have proven effective in certain lymphomas. 7,9,10 However, their efficacy is limited by incomplete inhibition of mTOR complex 1 (mTORC1) and by activation of AKT and downstream prosurvival pathways through a variety of feedback mechanisms.…”

“…1,3,[5][6][7][8][9][10][11] Over the last decade, rapamycin-based mTOR inhibitors have proven effective in certain lymphomas. 7,9,10 However, their efficacy is limited by incomplete inhibition of mTOR complex 1 (mTORC1) and by activation of AKT and downstream prosurvival pathways through a variety of feedback mechanisms. 6,[11][12][13][14][15] To overcome this limitation, inhibitors targeting the kinase activities of both mTORC1 and mTORC2 have been developed.…”

Phosphorylation-Dependent Inhibition of Akt1

“…Over-active Akt1 is a hallmark of diverse human malignancies [3,4] and linked to reduced survival outcomes [5,6]. Indeed, Akt1 is as a leading drug target in cancer [7,8]. Over 300 clinical trials are completed or underway that involve targeting the Akt1 signaling pathway.…”